Understanding the relationships between FUS-BBB opening, neuroinflammation and the neurovascular response

项目摘要： 血脑屏障（BBB）是一种重要的保护结构，它严格控制着哪些生物制剂能够通过 从血液进入脑实质，排除毒素，但也阻止了几乎所有的交付 神经治疗学聚焦超声（FUS）是一种新兴的技术，它允许非超声成像的可能性。 BBB的侵入性和受控开放，用于递送否则不会到达大脑的治疗剂。 使用保守的方案，FUS-BBB开放程序目前正在临床试验中进行，安全， 成功地用于治疗几种神经系统疾病。扩展到更广泛的临床应用 将需要将治疗参数推入一个方案，其中安全性问题与继发性 BBB破坏的影响尚未完全了解。这些问题包括引发炎症和 免疫反应，以及我们小组最近证实的脑血流调节的改变。在这 我们的项目旨在了解FUS-BBB开放，神经炎症和改变之间的关系。 脑血流调节，使FUS-BBB开放的领域可以安全地向前移动到新的 应用.我们将使用最先进的光学成像技术直接测量神经元，星形胶质细胞， FUS-BBB开放后神经血管反应的血流成分。标志物 在成像后立即收集的脑样品中评估炎症反应。数据将 在一系列强度、时间点和药物作用下获得，以阐明 连接FUS-BBB开放、神经炎症和神经血管反应的抑制。在目标1中， 关注FUS-BBB开放后神经元和星形胶质细胞活性的作用，以及它们的变化如何影响神经元和星形胶质细胞的活性。 信号传导可以影响神经血管反应的血流成分。在目标2中，我们将定义 急性神经炎症标志物与神经血管反应衰减之间的关系， 包括在FUS-BBB开放时给予的抗炎药的作用。在目标3中， 研究重复FUS-BBB开放对这些基本过程的影响，包括测试 假设预先调节炎症过程将允许随后实现BBB开放 一个沉默的回应。该项目将提供关于以下关系的重要新知识： FUS-BBB开放、炎症反应和神经血管反应的衰减。获得这种 知识对于安全地推动FUS-BBB领域进入新的临床应用至关重要。

Project Summary: The blood-brain barrier (BBB) is a critical protective structure that tightly controls which biologics are able to pass from the blood stream into the brain parenchyma, excluding toxins but also preventing the delivery of almost all neurotherapeutics. Focused ultrasound (FUS) is an emerging technology that allows the possibility of non- invasive and controlled opening of the BBB for delivery of therapeutics that would not otherwise reach the brain. Using conservative protocols, FUS-BBB opening procedures are being done today in clinical trials, safely and successfully, for treatment of several neurological diseases. Expansion to a wider range of clinical applications will require treatment parameters to be pushed into a regime where the safety concerns related to secondary effects of BBB disruption are not fully understood. These concerns include the initiation of inflammatory and immune responses and, recently demonstrated by our group, alteration of cerebral blood flow regulation. In this project we aim to understand the relationships between FUS-BBB opening, neuroinflammation, and alteration of cerebral blood flow regulation so that the field of FUS-BBB opening can be moved forward safely into new applications. We will use state of the art optical imaging techniques to directly measure the neuronal, astrocytic, and blood flow components of the neurovascular response following FUS-BBB opening. Markers of the inflammatory response will be assessed in brain samples collected immediately after imaging. The data will be acquired over a range of intensities, time points, and drug effects in order to elucidate the key mechanisms that link FUS-BBB opening, neuroinflammation, and the suppression of the neurovascular response. In Aim 1 we will focus on the role of neuronal and astrocytic activity following FUS-BBB opening and how changes in their signaling can affect the blood flow component of the neurovascular response. In Aim 2 we will define the relationships between markers of acute neuroinflammation and the attenuation of the neurovascular response, including the effects of an anti-inflammatory drug given at the time of FUS-BBB opening. In Aim 3 we will investigate the effects of repeated FUS-BBB opening on these fundamental processes, including testing the hypothesis that pre-conditioning the inflammatory process will allow subsequent BBB openings to be achieved with a muted response. This project will deliver significant new knowledge regarding the relationship between FUS-BBB opening, the inflammatory response, and attenuation of the neurovascular response. Gaining this knowledge is critical for safely driving the field of FUS-BBB opening into new clinical applications.